PROJECT SUMMARY Metabolic dysregulation due to in utero and early-life environmental exposures has lasting consequences on the developing immune system and lung and that these changes underlie the pathobiology of childhood atopy and wheeze. However, significant gaps remain in understanding the dysregulated metabolic-immune pathways and mechanisms involved in early childhood atopy and wheeze. Our preliminary study of the infant untargeted metabolome demonstrated that dysregulation in the unconjugated bilirubin (UCB) and lipid mediator's pathway are associated with number of wheeze episodes in a dose-response manner, which suggests the involvement of endogenous antioxidant and lipid mediator pathways. In another preliminary study of the infant immunome, we demonstrated that two distinct infant immune response profiles to acute respiratory infection, with an immune response pattern characterized by increased Type-2 and Type-17 and decreased non-interferon Type- 1 immune responses to with increased risk of recurrent wheeze. While these single omics studies can identify dysregulated metabolites and immune-responses in wheeze phenotypes, they alone fail to capture the full spectrum of underlying pathobiology. The integration of omics data has advanced the understanding of other chronic disease pathogenesis, as it is likely to do for childhood atopy and wheeze. Therefore, we hypothesize that the integration of early-life metabolome (including lipidome) and immunome can elucidate molecular pathways relevant to atopy and wheeze development. To test this hypothesis, the candidate will capitalize on existing carefully phenotyped population-based birth cohort of healthy infants (INSPIRE) and a replication cohort from the NIH ECHO initiative (ECHO-CREW asthma consortium) and accomplish the following specific aims: 1) To investigate whether increased unconjugated bilirubin (UCB) levels reduce early life atopy and wheeze incidence by enhancing the bioavailability of pro-resolving lipid mediators and antioxidants and decreasing pro-inflammatory lipid mediators, 2) To discover novel immunome profiles and network modules that characterize atopy and wheeze phenotypes, and 3) To uncover novel metabolic-immune molecular pathways associated with the development of atopy and wheeze phenotypes by integrating metabolome and immunome data. Successful completion of these aims will: (1) provide novel insights into the role of the early- life metabolome and immunome in the pathogenesis of atopy and wheeze and (2) identify targets for disease prevention. The proposal builds on the candidate's previous work, expertise, and interest in systems approaches to understand disease development. The goal of this career development proposal is for the candidate to emerge as an independent investigator in the field of asthma and allergy with unique knowledge and application of systems approaches to understand disease mechanisms. The candidate is in an outstanding academic environment, has a well thought out training and research plan, which will propel him into an independent expert in the field of immuno-metabolism of atopy and asthma.